Aminopropoxy-chromones useful as antidepressants

ABSTRACT

Basic ethers of the formula ##STR1## wherein Z is CH 3  --NR 2  --CH 2  CH 2  --CHR 1  --, (1-R 2  -3-piperidyl)-CHR 3  --, (1-R 2  -2-piperidyl)--CH 2  --CHR 3  -- or 1-R 2  -3-R 4  -hexahydroazepinyl; R 1  is cyclopropyl or Ar; R 2  is H, alkyl of 1-4 C atoms, alkenyl of 2-4 C atoms, cycloalkylalkyl of 4-8 C atoms or benzyl; R 3  is H or Ar; R 4  is H or alkyl of 1-4 C atoms, Y is --O--CHQ 1  --CHQ 2  --CH 2  --, --O--CHQ 1  --CHQ 2  --CO--, --O--CQ 1  ═CQ 2  --CO-- or --CH 2  --CHQ 1  --CHQ 2  --CO--; Q 1  and Q 2  are independently each H, alkyl of 1-4 C atoms, cycloalkyl or alkylcycloalkyl each of 3-6 total C atoms or Ar; and Ar is phenyl or phenyl substituted by F, Cl, alkoxy or alkylthio, each of 1-4 C atoms, methylenedioxy or CF 3  ; with the proviso that when Z is (CH 3 ) 2  N--CH 2  CH 2  --CHR 1  in 7-position and Y is --O--C(C 6  H 5 )═CH--CO-- or --O--C(C 6  H 5 )═C(CH 3 )--CO--, R 1  is cyclopropyl, or phenyl substituted by F, Cl, alkoxy or alkylthio, each of 1-4 C atoms, methylenedioxy or CF 3  ; 
     or a physiologically acceptable acid addition salt thereof, have valuable pharmacological properties, e.g., are antidepressants.

This is a division of application Ser. No. 700,226, filed 2/11/85, nowabandoned, which is a division of Ser. No. 459,928, filed 1/21/83, nowU.S. Pat. No. 4,508,732, issued 4/2/85, which is a division of Ser. No.216,454, filed 12/15/80, now U.S. Pat. No. 4,376,123, issued 3/8/83.

BACKGROUND OF THE INVENTION

The present invention relates to new basic ethers having valuablepharmacological properties.

Certain related compounds are known from the Journal fur praktischeChemie, Volume 311, pages 183 to 186 (1969), in particular7-(1-phenyl-3-dimethylaminopropoxy)-flavone and3-methyl-7-(1-phenyl-3-dimethylaminopropoxy)-flavone. However, it isstated in this reference that the disclosed substances exhibit "nopharmacodynamically usable properties". In light of this statement, thevaluable pharmacological properties of the present new compounds areparticularly surprising.

SUMMARY OF THE INVENTION

It is an object of this invention to provide new compounds which can beused for the preparation of medicaments.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained by providing new basic ethers ofFormula I ##STR2## wherein Z is CH₃ --NR² --CH₂ CH₂ --CHR¹ --, (1-R²-3-piperidyl)-CHR³ --, (1-R² -2-piperidyl)--CH₂ --CHR³ -- or 1-R² -3-R⁴-4-hexahydroazepinyl; R¹ is cyclopropyl or Ar; R² is H, alkyl of 1-4Catoms, alkenyl of 2-4C atoms, cycloalkylalkyl of 4-8C atoms or benzyl;R³ is H or Ar; R⁴ is H or alkyl of 1-4C atoms; Y is --O--CHQ¹ --CHQ²--CH₂ --, --O--CHQ¹ --CHQ² --CO--, --O--CQ¹ ═CQ² --CO-- or --CH₂ --CHQ¹--CHQ² --CO--; Q¹ and Q² are independently each H, alkyl of 1-4C atoms,cycloalkyl of 3-6C atoms or Ar; and Ar is phenyl or phenyl substitutedby F, Cl, alkoxy or alkylthio, each of 1-4C atoms, methylenedioxy or CF₃; with the proviso that when Z is (CH₃)₂ N--CH₂ CH₂ --CHR¹ in 7-positionand Y is --O--C(C₆ H₅)═CH--CO-- or --O--C(C₆ H₅)═C(CH₃)--CO--, R¹ iscyclopropyl or phenyl which is substituted by F, Cl, alkoxy or alkylthioeach of 1-4C atoms, methylenedioxy or CF₃ ;

and the physiologically acceptable acid addition salts thereof.

DETAILED DISCUSSION

The invention relates to the basic ethers of Formula I and to theirphysiologically acceptable acid addition salts.

In R², R⁴, Q¹ and Q², alkyl is preferably methyl, and also ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.Cycloalkyl (in the radicals Q¹ and Q²) is preferably cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl and also 1-methylcyclopropyl,2-methylcyclopropyl, 1-, 2- or 3-methylcyclobutyl, 1-, 2- or3-methylcyclopentyl, 1-ethylcyclopropyl or 2-ethylcyclopropyl and thelike. Alkoxy (in the radical Ar) is preferably methoxy and also ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.Alkenyl (in the radical R²) is preferably allyl and is also vinyl,propenyl, isopropenyl, 1-butene-1-yl, 1-butene-2-yl, 2-butene-1-yl,2-butene-2-yl, 3-butene-1-yl, 3-butene-2-yl, 2-methyl-1-propene-1-yl,2-methyl-1-propene-2-yl or 2-methyl-2-propene-1-yl. Cycloalkylalkyl (inthe radical R²) is preferably cyclopropylmethyl, but is also, forexample, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-, 2- or3-cyclopropylpropyl, 1-cyclopropyl-1-methylethyl, 1-, 2-, 3- or4-cyclopropylbutyl, 1-cyclopropyl-1-methylpropyl, 1-, 2-, 3-, 4- or5-cyclopropylpentyl, cyclobutylmethyl, 1-cyclobutylethyl,2-cyclobutylethyl, 1-, 2- or 3-cyclobutylpropyl, 1-, 2-, 3- or4-cyclobutylbutyl, cyclopentylmethyl, 1-cyclopentylethyl,2-cyclopentylethyl, 1-, 2- or 3-cyclopentylpropyl, cyclohexylmethyl,1-cyclohexylethyl, 2-cyclohexylethyl or cycloheptylmethyl. Alkylthio (inthe radical Ar) is preferably methylthio, but is also ethylthio,n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio ortert-butylthio.

The radical Ar is preferably phenyl and secondarily p-fluorophenyl,p-chlorophenyl, p-methoxyphenyl, 3,4-methylenedioxyphenyl orm-trifluoromethylphenyl, and also o-fluorophenyl, m-fluorophenyl,o-chlorophenyl, m-chlorophenyl, o-methoxyphenyl, m-methoxyphenyl, o-, m-or p-methylthiophenyl, 2,3-methylenedioxyphenyl, o-trifluoromethylphenylor p-trifluoromethylphenyl. If several radicals Ar are present in thesame molecule, they can be identical or different from one another.

In detail, R¹ is preferably phenyl, p-fluorophenyl, p-chlorophenyl orp-methoxyphenyl; R² is preferably H or methyl and secondarily ispreferably ethyl, allyl, cyclopropylmethyl or benzyl; R³ is preferably Hor phenyl; and R⁴ is preferably H or methyl.

Accordingly, the radical Z is preferably 1-phenyl-3-dimethylaminopropyland secondarily is preferably 1-phenyl-3-methylaminopropyl,1-phenyl-3-N-benzyl-N-methylaminopropyl, (3-piperidyl)-methyl,α-(3-piperidyl)-benzyl, (1-methyl-3-piperidyl)-methyl,α-(1-methyl-3-piperidyl)-benzyl, 2-(2-piperidyl)-ethyl,1-phenyl-2-(2-piperidyl)-ethyl, 2-(1-methyl-2-piperidyl)-ethyl,1-phenyl-2-(1-methyl-2-piperidyl)-ethyl, 4-hexahydroazepinyl,1-methyl-4-hexahydroazepinyl, 3-methyl-4-hexahydroazepinyl and1,3-dimethyl-4-hexahydroazepinyl, and also, for example,1-phenyl-3-methylethylaminopropyl,1-phenyl-3-(N-methyl-N-allylamino)-propyl,1-phenyl-3-(N-methyl-N-cyclopropylmethylamino)-propyl,(1-ethyl-3-piperidyl)-methyl, α-(1-ethyl-3-piperidyl)benzyl,(1-allyl-3-piperidyl)-methyl, α-(1-allyl-3-piperidyl)-benzyl,(1-cyclopropylmethyl-3-piperidyl)-methyl,α-(1-cyclopropylmethyl-3-piperidyl)-benzyl,(1-benzyl-3-piperidyl)-methyl, α-(1-benzyl-3-piperidyl)-benzyl,2-(1-ethyl-2-piperidyl)-ethyl, 1-phenyl-2-(1-ethyl-2-piperidyl)-ethyl,2-(1-allyl-2-piperidyl)-ethyl, 1-phenyl-2-(1-allyl-2-piperidyl)-ethyl,2-(1-cyclopropylmethyl-2-piperidyl)-ethyl,1-phenyl-2-(1-cyclopropylmethyl- 2-piperidyl)-ethyl,2-(1-benzyl-2-piperidyl)-ethyl, 1-phenyl-2-(1-benzyl-2-piperidyl)-ethyl,3-ethyl-4-hexahydroazepinyl, 1-methyl-3-ethyl-4-hexahydroazepinyl,1-ethyl-4-hexahydroazepinyl, 1-allyl-4-hexahydroazepinyl,1-cyclopropylmethyl-4-hexahydroazepinyl or 1-benzyl-4-hexahydroazepinyl,1-cyclopropyl-3-methylaminopropyl, 1-p-fluorophenyl-3-methylaminopropyl,1-p-chlorophenyl-3-methylaminopropyl,1-m-trifluoromethylphenyl-3-methylaminopropyl,1-cyclopropyl-3-dimethylaminopropyl,1-p-fluorophenyl-3-dimethylaminopropyl,1-p-chlorophenyl-3-dimethylaminopropyl or1-m-trifluoromethylphenyl-3-dimethylaminopropyl.

The radicals Q¹ and Q² can be identical or different. Preferably one ofthese radicals is H or alkyl of 1-3C atoms and the other is H or Ar, Arbeing, in particular, phenyl, p-fluorophenyl, p-chlorophenyl,p-methoxyphenyl, 3,4-methylenedioxyphenyl or m-trifluoromethylphenyl.

The radical Y is, accordingly, preferably --O--CHQ³ --CHQ⁴ --CH₂ --(wherein the radicals Q³ and Q⁴ are each H or alkyl of 1-3C atoms, butone of these radicals preferably is H; chromans), --O--CHAr--CHQ⁴ --CH₂--(flavans), --O--CHQ³ --CHAr--CH₂ -- (iso-flavans), --O--CHQ³ --CHQ⁴--CO-- (chromanones), --O--CHAr--CHQ⁴ --CO-- (flavanones), --O--CHQ³--CHAr--CO-- (iso-flavanones), --O--CQ³ ═CQ⁴ --CO-- (chromones),--O--CAr═CQ⁴ --CO-- (flavones), --O--CQ³ ═CAr--CO-- (isoflavones) or--CH₂ --CHQ³ --CHQ⁴ --CO-- (tetralones). Among these, the isoflavonesare particularly preferred and secondarily the tetralones and theflavones.

Accordingly, the invention relates particularly to those compounds ofthe Formula I in which at least one of the mentioned radicals has one ofthe meanings indicated above, especially one of the preferred meaningsindicated above. Some preferred groups of compounds can be expressed bymeans of the partial Formulae Ia to Ic which follow, which correspond tothe Formula I, and wherein the radicals not designated in greater detailhave the meanings indicated for Formula I, but wherein: in Ia: Z is CH₃--NR² --CH₂ CH₂ --CHR¹ --; R¹ is phenyl; R² is H, methyl or benzyl; Y is--O--CH₂ CH₂ CH₂ --, --O--CHAr--CH₂ CH₂ --, --O--CH₂ --CH(C₆ H₅)--CH₂--, --O--CH₂ CH₂ --CO--, --O--CHAr--CHQ⁴ --CO--, --O--CAr═CQ⁴ --CO--,--O--CH═CAr--CO-- or --CH₂ CH₂ CH₂ --CO--, Ar is phenyl, p-fluorophenyl,p-chlorophenyl, p-methoxyphenyl, 3,4-methylenedioxyphenyl orm-trifluoromethylphenyl; and Q⁴ is H or alkyl of 1-3C atoms; in Ib: Z isCH₃ --NR² --CH₂ CH₂ --CHR¹ ; R¹ is phenyl; R² is H, methyl or benzyl;and Y is --O--C(C₆ H₅)═CH--CO--, --O--CH═C(C₆ H₅)--CO-- or --CH₂ CH₂ CH₂--CO--; and in Ic: Z is CH₃ --NR² --CH₂ CH₂ --CHR¹ --; R¹ is phenyl; R²is H, methyl or benzyl; and Y is --O--CH═C(C₆ H₅)--CO--.

The compounds of Formula I can contain one or more asymmetric carbonatoms. They can therefore exist in the form of racemates and, if severalasymmetric carbon atoms are present, also in the form of mixtures ofseveral racemates, as well as in various optically active forms.

The present invention relates further to a process for preparing thecompounds of Formula I and their physiologically acceptable acidaddition salts, comprising reacting a phenol of Formula II

    HO--G                                                      II

wherein G is the group ##STR3## or one of its salts, with an amine ofFormula III

    Z-X                                                        III

wherein X is Cl, Br, I or OH and Z is as defined above, or with one ofits reactive derivatives; and, if appropriate, in a resulting compoundof Formula I, converting a secondary amino group by treatment with analkylating, alkenylating, cycloalkylating or benzylating agent into thecorresponding tertiary amino group, or converting an N-benzyl group bytreatment with a reducing agent into an NH group, and/or converting aresulting base of Formula I by treatment with an acid into one of itsphysiologically acceptable acid addition salts.

The preparation of the compounds of Formula I is effected in otherrespects in accordance with methods which are in themselves known suchas are described in the literature (for example in the standard workssuch as Houben-Weyl, Methoden der Organischen Chemie ("Methods ofOrganic Chemistry"), Georg-Thieme-Verlag, Stuttgart; or OrganicReactions, John Wiley and Sons, Inc., New York) and, in particular,under reaction conditions such as are known and suitable for thesereactions. In these reactions it is also possible to make use ofvariants which are in themselves known, but are not described in greaterdetail herein.

The starting materials of Formulae II and III can, if desired, also beformed in situ, in such a way that they are not isolated from thereaction mixture, but are immediately reacted further to produce thecompounds of Formula I.

The phenols of Formula II are in most cases known. When they are new,they can be prepared by methods which are in themselves known, forexample by splitting corresponding benzyl or methyl ethers.

In the bases of Formula III, the radical X is preferably Cl or Br.Reactive derivatives of these bases include, in particular, the reactiveesters of the alcohols of Formula III (X=OH), preferably thecorresponding alkylsulfonates (wherein the alkyl group is of 1-6C atoms)and the corresponding arylsulfonates (wherein the aryl group is of 6-10Catoms), for example the corresponding methanesulfonates,benzenesulfonates, p-toluenesulfonates, naphthalene-1-sulfonates ornaphthalene-2-sulfonates.

Some of the bases of Formula III are known. Those bases of Formula IIIwhich have not been disclosed hitherto can be prepared by methods whichare in themselves known in analogy to their use with known compounds.Thus the compounds of Formula III (X═OH) can be obtained, for example,by reducing corresponding esters or ketones of the type CH₃ --NR² --CH₂CH₂ --CO--R¹, (1-R² -3-piperidyl)--COO--alkyl, (1-R²-3-piperidyl)--CO--R³, (1-R² -2-piperidyl)--CH₂ --COO--alkyl, (1-R²-2-piperidyl)--CH₂ --CO--R³ or 1-R² -3-R⁴ -hexahydroaze-pin-4-one, whilethe compounds of Formula III (X=Cl, Br or I) can be obtained from thealcohols by means of inorganic halides, such as SOCl₂, PBr₃ or HI, andthe sulfonates can be obtained by esterifying the alcohols with thecorresponding sulfonyl chlorides. The tertiary amines among those ofFormula III (in which R² is not H) are also accessible from thesecondary amines (III, R² =H) by alkylation, alkenylation,cycloalkylalkylation or benzylation. Conversely, the secondary amines(III, R² =H) can be obtained from the corresponding N-alkyl derivatives(III, R² =alkyl having 1-4C atoms) by dealkylation by means ofchloroformic acid ethyl ester. Furthermore, the amines of Formula IIIcan be prepared by reducing corresponding pyridines or azepines. Thus,for example, it is possible to metallize 2-methylpyridine with C₆ H₅ Li,subsequently to react the product with benzaldehyde to give1-phenyl-2-(2-pyridyl)-ethanol and to reduce the latter to give1-phenyl-2-(2-piperidyl)-ethanol. 1-Methyl-4-hydroxy-hexahydroazepine isaccessible by ring enlargement of 1-methyl-4-piperidone by means of CH₂N₂ to give 1-methyl-hexahydroazepin-4-one and reduction of the latterusing NaBH₄.

Before the reaction with III, the phenol II is preferably firstconverted into a salt, particularly into a metal salt, for example analkali metal salt (Li, Na or K salt) or a thallium salt. The phenol canbe reacted with a reagent which forms metal salts, for example an alkalimetal (for example Na), an alkali metal hydride or amide (for exampleLiH, NaH, NaNH₂ or KNH₂), a metal alcoholate (wherein the alcohol partpreferably has 1-4C atoms, for example lithium methylate, ethylate ortert-butylate, sodium methylate, ethylate or tert-butylate, potassiummethylate, ethylate or tert-butylate or thallium methylate, ethylate ortert-butylate), an organo-metallic compound (for example butyllithium,phenyllithium or phenylsodium) or a metal hydroxide, carbonate orbicarbonate (for example of Li, Na, K or Ca). The preparation of thephenolate is advantageously effected in the presence of a solvent ormixture of solvents. Examples of suitable solvents are hydrocarbons(such as hexane, benzene, toluene or xylene), halogenated hydrocarbons(such as CH₂ Cl₂, CHCl₃ or CCl₄), ethers (such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF), dioxane or diethylene glycoldimethyl ether), amides, such as dimethylformamide (DMF), alcohols (suchas methanol or ethanol) or ketones (such as acetone or butanone).

The phenol II, or its salt, is preferably reacted with the amine III inthe presence of a diluent, for example the solvent which has been usedfor the preparation of the salt, but this can be replaced by anothersolvent or diluted with another solvent. A particular variant consistsin carrying out the reaction in two phases (for example in CH₂ Cl₂/aqueous sodium hydroxide solution), in which case it is also possibleto add a catalyst (for example a crown ether, an ammonium salt, such asa trialkylbenzylammonium halide or a phosphonium salt). The reaction isgenerally carried out at temperatures of about -20° to 180° C.,preferably 20° to 160° C.

The phenolate can also be formed in situ. In this case the phenol II andthe amine III are allowed to react with one another in the presence of abase.

A variant of the reaction consists in reacting a phenol of Formula IIwith a hydroxyamine of Formula III (X=OH) in the presence of adehydrating agent, for example an azodicarboxylic acid dialkyl ester, inthe presence of triphenylphosphine in an inert solvent, such as THF, atabout -10° to +30° C.

Furthermore, it is possible, if desired, to alkylate a resultingsecondary amine of Formula I (R² =H) on the nitrogen atom, in which casetertiary amines of Formula I (R² =alkyl having 1-4C atoms) are obtained.Examples of suitable N-alkylating agents are the corresponding alkylhalides, for example methyl chloride, methyl bromide, methyl iodide,ethyl chloride, ethyl bromide, ethyl iodide and n-propyl chloride,bromide or iodide and the like, and also the corresponding dialkylsulfates, such as dimethyl sulfate, and the corresponding sulfonic acidalkyl esters, such as p-toluenesulfonic acid methyl ester. A methylgroup can also be introduced, for example by treatment with formic acidand aqueous formaldehyde solution, preferably by heating for severalhours at temperatures of 50° to 100° C. In general, the N-alkylation ispreferably effected in the presence or absence of an inert solvent attemperatures of about 0° to about 120° C., preferably of 40° to 100° C.,and it is also possible for a catalyst to be present, preferably a basesuch as potassium tert-butylate.

It is also possible to carry out alkylation by treating a secondary baseI (R² =H) with an aldehyde or ketone in the presence of hydrogen and ahydrogenation catalyst (for example Raney nickel) at temperatures ofabout 50° to 100° C. and pressures of about 1 to 200 atmospheres; thus,using acetone, the corresponding isopropyl compound I (R² =isopropyl) isobtained.

It is also possible to carry out alkylation in several stages. Forexample, a compound of Formula I (R² =H) can first be acylated in amanner which is in itself known (for example acylated by treatment withacetic anhydride/pyridine) and the resulting N-acylation product (forexample N-acetylation product) can then be reduced to give the desiredtertiary amine, for example by means of a complex metal hydride, such asLiAlH₄, in an inert solvent, such as diethyl ether or THF, preferably attemperatures of 20° to 60° C.

A secondary amine of Formula I (R² =H) can be treated in a completelyanalogous manner with alkenylating, cycloalkylalkylating or benzylatingagents (for example alkenyl halides, such as allyl chloride or bromide,cyclopropylmethyl halides, such as cyclopropylmethyl chloride orbromide, or benzyl halides, such as benzyl chloride or bromide), inwhich case compounds of Formula I (R² =alkenyl of 2-4C atoms,cycloalkylalkyl of 4-8C atoms or benzyl) are formed.

Furthermore, in a compound of Formula I (R² =benzyl), the benzyl groupcan be removed by reduction by a method indicated in the literature,preferably by hydrogenolysis in the presence of a noble metal catalystor with the aid of a dealkylating agent, for example ClCOOC₂ H₅ /NaOH.

A resulting base of Formula I can be converted by means of an acid intothe appropriate acid addition salt. Acids suitable for this reaction arethose which provide physiologically acceptable salts. Thus it ispossible to use inorganic acids, for example sulfuric acid, hydrogenhalide acids, such as hydrochloric acid or hydrobromic acid, phosphoricacids, such as orthophosphoric acid, nitric acid or sulfamic acid, andalso organic acids, in particular aliphatic, alicyclic, araliphatic,daromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic orsulfuric acids, such as formic acid, acetic acid, propionic acid,pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelicacid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,benzoic acid, salicyclic acid, 2-phenylpropionic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, naphthalenemonosulfonic acid, naphthalenedisulfonic acid andlaurylsulfuric acid.

The free bases of Formula I can, if desired, be liberated from theirsalts by treatment with strong bases, such as sodium hydroxide orcarbonate or potassium hydroxide or carbonate.

It has been found that the compounds of Formula I and theirphysiologically acceptable acid addition salts possess valuablepharmacological properties. Thus they exhibit, in particular, effects onthe central nervous system, above all anti-depressant activity. Indetail, it is possible to demonstrate a reserpine-antagonistic action(which can be detected, for example on mice, in respect of reserpine, bya technique modeled on the method of Askew, Life Science, Volume 10(1963), pages 725-730), an anticataleptic action (which can be detected,for example on rats, in respect of tetrabenazine, by a technique modeledon the method of Giurgea et al., Medicina Experimentalis, Volume 9,(1963), pages 249-262) and an antiptotic action (which can be detected,for example in respect of reserpine, by a technique modeled on themethodology of Domenjoz and Theobald, Arch. int. pharmacodyn., Volume120 (1959), pages 450 et seq., using the evaluation according to Rubinet al., J. Pharmacol. Exp. Therap., Volume 120 (1957), pages 125-136).Furthermore, the action of 5-hydroxy-tryptophan in mice (method similarto that of Ross et al., Acta pharmacol. et toxicol., Volume 39 (1976),pages 152-166) can be potentiated, and the effects on the centralnervous system of excitation and increase in temperature, which can beinitiated by D-amphetamine sulfate (for example 1.5 mg/kg administeredsubcutaneously 1 hour after the test substance, which is alsoadministered subcutaneously) and aggregation (putting 5 rats together ina glass container) (methodology according to Muller-Calgan et al., inZippel, H. P. (ed.): Memory and Transfer of Information, Plenum Press,New York-London, 1973, pages 87-125), can be increased and/or prolonged.The substances have an effect on the biogenous amines of ZNS. Thus, forexample, in vitro they lead to inhibition of the absorption ofnor-adrenalin, 5-hydroxytryptamine and dopamine (methodology:Kannegieβer et al., Biochem. Pharmacol., Volume 22 (1973), pages 73-84)in synaptosomes, and in vivo they inhibit the liberation, within thebrain, of catecholamine and serotonin which is induced by tyraminederivatives (methodology: Carlsson et al., Europ. J. Pharmacol., Volume5 (1969) , pages 357-366; 367-373). A hypotensive action and aspasmolytic action are also produced, and these can be determined bymethods in current use for this purpose.

Compounds of Formula I and their physiologically acceptable acidaddition salts can, therefore, be used as medicinally active compoundsand also as intermediate products for the preparation of othermedicinally active compounds.

Thus, the invention further relates to the use of the compounds ofFormula I and their physiologically acceptable salts for the preparationof pharmaceutical formulations, particularly by a non-chemical route. Inthis connection they can be brought into a suitable dosage form togetherwith at least one excipient or adjuvant and, if appropriate, incombination with one or more other active compound(s).

The present invention further relates to agents, especiallypharmaceutical formulations, containing a compound of Formula I and/orone of its physiologically acceptable acid addition salts. Theseformulations can be employed as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral) or parenteral administrationor for local application, and which do not react with the new compounds,for example water, vegetable oils, benzyl alcohols, polyethyleneglycols, gelatines, carbohydrates, such as lactose or starch, magnesiumstearate, talc or petroleum jelly. Tablets, dragees, capsules, syrups,elixirs, drops or suppositories are especially used for enteraladministration; solutions, preferably oily or aqueous solutions, andalso suspensions, emulsions or implants are especially used forparenteral administration; and ointments, creams or powders areespecially used for topical application. The new compounds can also belyophilized and the resulting lyophilizates can be used, for example,for the preparation of injection preparations. The formulationsindicated can be sterilized and/or can contain adjuvants, such aslubricants, preservatives, stabilizing agents and/or wetting agents,emulsifiers, salts for regulating the osmotic pressure, buffersubstances, colorants, flavoring substances and/or aroma generatingsubstances. If desired, they can also contain one or more additionalactive compounds, for example one or more vitamins.

The invention further relates to the use of the compounds of Formula Iand their physiologically acceptable acid addition salts in combatingdiseases, particularly depressions of various etiologies andsymptomatologies, and to their use in the therapeutic treatment of thehuman or animal body.

In this connection, the substances of this invention are generallyadministered in a manner analogous to that of knownpsychopharmacological agents which are commercially available (forexample Imipramine), preferably in dosages of about 2-500 mg,particularly of 10-50 mg, per dosage unit. The daily dosage ispreferably about 0.05 to 10 mg/kg of body weight. The particular dosefor each specific patient depends, however, on a very wide variety offactors, for example on the activity of the particular compoundemployed, on the age, body weight, general state of health, sex, anddiet of the patient, on the time and route of administration, on theexcretion rate and combination of medicaments and on the severity of theparticular disease to which the therapy applies. Oral administration ispreferred.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingexamples, all temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

Each of the compounds of Formula I mentioned in the examples whichfollow is particularly suitable for the preparation of pharmaceuticalformulations.

In the following examples, "customary working-up" denotes:

Water is added if necessary, the mixture is extracted with an organicsolvent, such as benzene, chloroform or methylene chloride, the phasesare separated and the organic phase is dried over sodium sulfate, themixture is filtered, the filtrate is evaporated and the product ispurified by chromatography and/or crystallization.

The Rf values were obtained on silica gel using 8:2toluene/triethylamine, unless otherwise indicated.

EXAMPLE 1

A solution of 23.8 g of 7-hydroxyisoflavone in 250 ml of 0.5N ethanolicKOH is evaporated, the residue is dissolved in 200 ml of DMF and thesolution is heated to 150°; a solution of 20 g of1-chloro-1-phenyl-3-dimethylaminopropane in 50 ml of DMF is added, whilestirring. The mixture is stirred for 1.5 hours at 150° and7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone is precipitated by addingwater. M.p. 128°-130° (from acetone). Hydrochloride, m.p. 259°-260°.

EXAMPLES 2 TO 220

The following are obtained analogously to Example 1 by etherifying theNa salts of 6-hydroxychroman, 7-hydroxychroman, 6-hydroxyflavan,7-hydroxyflavan, 6-hydroxyisoflavan, 7-hydroxyisoflavan,6-hydroxychromanone, 7-hydroxychromanone, 6-hydroxyflavanone,7-hydroxyflavanone, 6-hydroxyisoflavanone, 7-hydroxyisoflavanone,6-hydroxychromone, 7-hydroxychromone, 5-, 6-, 7- or 8-hydroxyflavone,5-, 6-, 7- or 8-hydroxyisoflavone or 5-, 6- or 7-hydroxytetralone with1-chloro-1-phenyl-3-methylaminopropane,1-chloro-1-phenyl-3-dimethylaminopropane,1-chloro-1-phenyl-3-N-benzyl-N-methylaminopropane,3-chloromethylpiperidine, 3-(α-chlorobenzyl)-piperidine,1-methyl-3-chloromethylpiperidine,1-methyl-3-(α-chlorobenzyl)-piperidine, 2-(2-chloroethyl)-piperidine,2-(2-chloro-2-phenylethyl)-piperidine,1-methyl-2-(2-chloroethyl)-piperidine,1-methyl-2-(2-chloro-2-phenylethyl)-piperidine,1-benzyl-2-(2-chloroethyl)-piperidine, 4-chlorohexahydroazepine,1-methyl-4-chlorohexahydroazepine, 3-methyl-4-chlorohexahydroazepine and1,3-dimethyl-4-chlorohexahydroazepine or the corresponding brominecompounds:

2. 6-(1-Phenyl-3-methylaminopropoxy)-chroman, hydrochloride, m.p. 164°.

3. 7-(1-Phenyl-3-methylaminopropoxy)-chroman.

4. 6-(1-Phenyl-3-dimethylaminopropoxy)-chroman, hydrochloride, m.p.137°-139°.

5. 7-(1-Phenyl-3-dimethylaminopropoxy)-chroman, hydrochloride, m.p.182°-183°.

6. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chroman, hydrochloride,m.p. 139°-140°.

7. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chroman.

8. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chroman.

9. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chroman.

10. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-chroman, hydrochloride, m.p.100°-103°.

11. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-chroman.

12. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chroman.

13. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chroman.

14. 6-(1-Phenyl-3-methylaminopropoxy)-flavan.

15. 7-(1-Phenyl-3-methylaminopropoxy)-flavan.

16. 6-(1-Phenyl-3-dimethylaminopropoxy)-flavan.

17. 7-(1-Phenyl-3-dimethylaminopropoxy)-flavan.

18. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-flavan.

19. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-flavan.

20. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-flavan.

21. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-flavan.

22. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavan.

23. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavan.

24. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavan.

25. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavan.

26. 6-(1-Phenyl-3-methylaminopropoxy)-isoflavan.

27. 7-(1-Phenyl-3-methylaminopropoxy)-isoflavan.

28. 6-(1-Phenyl-3-dimethylaminopropoxy)-isoflavan.

29. 7-(1-Phenyl-3-dimethylaminopropoxy)-isoflavan, m.p. 98°-100°.

30. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavan.

31. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavan.

32. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-isoflavan.

33. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-isoflavan.

34. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavan.

35. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavan.

36. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavan.

37. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavan.

38. 6-(1-Phenyl-3-methylaminopropoxy)-chromanone.

39. 7-(1-Phenyl-3-methylaminopropoxy)-chromanone.

40. 6-(1-Phenyl-3-dimethylaminopropoxy)-chromanone, hydrochloride, m.p.188°-191°.

41. 7-(1-Phenyl-3-dimethylaminopropoxy)-chromanone.

42. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chromanone.

43. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chromanone.

44. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chromanone.

45. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chromanone.

46. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-chromanone.

47. 7-[2-(1-Methyl-2piperidyl)-ethoxy]-chromanone, hydrochloride, m.p.182°-184°.

48. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chromanone.

49. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chromanone.

50. 6-(1-Phenyl-3-methylaminopropoxy)-flavanone.

51. 7-(1-Phenyl-3-methylaminopropoxy)-flavanone.

52. 6-(1-Phenyl-3-dimethylaminopropoxy)-flavanone.

53. 7-(1-Phenyl-3-dimethylaminopropoxy)-flavanone.

54. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-flavanone.

55. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-flavanone.

56. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-flavanone.

57. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-flavanone.

58. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavanone.

59. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavanone.

60. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavanone.

61. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavanone.

62. 6-(1-Phenyl-3-methylaminopropoxy)-isoflavanone.

63. 7-(1-Phenyl-3-methylaminopropoxy)-isoflavanone.

64. 6-(1-Phenyl-3-dimethylaminopropoxy)-isoflavanone.

65. 7-(1-Phenyl-3-dimethylaminopropoxy)-isoflavanone.

66. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavanone.

67. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavanone.

68. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-isoflavanone.

69. 7-α-(1-Methyl-3-piperidyl)-benzyloxy]-isoflavanone.

70. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavanone.

71. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavanone.

72. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavanone.

73. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavanone.

74. 6-(1-Phenyl-3-methylaminopropoxy)-chromone.

75. 7-(1-Phenyl-3-methylaminopropoxy)-chromone.

76. 6-(1-Phenyl-3-dimethylaminopropoxy)-chromone.

77. 7-(1-Phenyl-3-dimethylaminopropoxy)-chromone, hydrochloride m.p.199°.

78. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

79. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

80. 6-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chromone.

81. 7-[α-(1-Methyl-3-piperidyl)-benzyloxy]-chromone.

82. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-chromone.

83. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-chromone.

84. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chromone.

85. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-chromone.

86. 5-(1-Phenyl-3-methylaminopropoxy)-flavone.

87. 6-(1-Phenyl-3-methylaminopropoxy)-flavone, Rf 0.43 (8:2 methylenechloride/triethylamine).

88. 7-(1-Phenyl-3-methylaminopropoxy)-flavone.

89. 5-(1-Phenyl-3-dimethylaminopropoxy)-flavone, m.p. 140°-141°.

90. 6-(1-Phenyl-3-dimethylaminopropoxy)-flavone, m.p. 142°-142.5°.

91. 8-(1-Phenyl-3-dimethylaminopropoxy)-flavone.

92. 5-(1-Phenyl-3-N-benzyl-N-methylamino)-flavone.

93. 6-(1-Phenyl-3-N-benzyl-N-methylamino)-flavone, m.p. 93°-94°.

94. 7-(1-Phenyl-3-N-benzyl-N-methylamino)-flavone.

95. 5-(3-Piperidyl-methoxy)-flavone.

96. 6-(3-Piperidyl-methoxy)-flavone.

97. 7-(3-Piperidyl-methoxy)-flavone.

98. 5-(α-3-Piperidyl-benzyloxy)-flavone.

99. 6-(α-3-Piperidyl-benzyloxy)-flavone.

100. 7-(α-3-Piperidyl-benzyloxy)-flavone.

101. 5-(1-Methyl-3-piperidyl-methoxy)-flavone.

102. 6-(1-Methyl-3-piperidyl-methoxy)-flavone.

103. 7-(1-Methyl-3-piperidyl-methoxy)-flavone.

104. 5-(α-1-Methyl-3-piperidyl-benzyloxy)-flavone.

105. 6-(α-1-Methyl-3-piperidyl-benzyloxy)-flavone.

106. 7-(α-1-Methyl-3-piperidyl-benzyloxy)-flavone.

107. 5-[2-(2-Piperidyl)-ethoxy]-flavone.

108. 6-[2-(2-Piperidyl)-ethoxy]-flavone.

109. 7-[2-(2-Piperidyl)-ethoxy]-flavone.

110. 5-[1-Phenyl-2-(2-piperidyl)-ethoxy]-flavone.

111. 6-[1-Phenyl-2-(2-piperidyl)-ethoxy]-flavone.

112. 7-[1-Phenyl-2-(2-piperidyl)-ethoxy]-flavone.

113. 5-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavone.

114. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavone.

115. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-flavone.

116. 5-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-flavone.

117. 6-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-flavone.

118. 7-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-flavone.

119. 5-(4-Hexahydroazepinyloxy)-flavone.

120. 6-(4-Hexahydroazepinyloxy)-flavone.

121. 7-(4-Hexahydroazepinyloxy)-flavone.

122. 5-(1-Methyl-4-hexahydroazepinyloxy)-flavone.

123. 6-(1-Methyl-4-hexahydroazepinyloxy)-flavone.

124. 7-(1-Methyl-4-hexahydroazepinyloxy)-flavone.

125. 5-(3-Methyl-4-hexahydroazepinyloxy)-flavone.

126. 6-(3-Methyl-4-hexahydroazepinyloxy)-flavone.

127. 7-(3-Methyl-4-hexahydroazepinyloxy)-flavone.

128. 5-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavone.

129. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavone.

130. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-flavone.

131. 5-(1-Phenyl-3-methylaminopropoxy)-isoflavone.

132. 6-(1-Phenyl-3-methylaminopropoxy)-isoflavone.

133. 7-(1-Phenyl-3-methylaminopropoxy)-isoflavone, hydrochloride, m.p.210°-211°.

134. 5-(1-Phenyl-3-dimethylaminopropoxy)-isoflavone.

135. 6-(1-Phenyl-3-dimethylaminopropoxy)-isoflavone.

136. 8-(1-Phenyl-3-dimethylaminopropoxy)-isoflavone.

137. 5-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavone.

138. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavon.

139. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavone, m.p.115°-118°. Hydrochloride, m.p. 210°-212°.

140. 5-(3-Piperidyl-methoxy)-isoflavone.

141. 6-(3-Piperidyl-methoxy)-isoflavone.

142. 7-(3-Piperidyl-methoxy)-isoflavone.

143. 5-(α-3-Piperidyl-benzyloxy)-isoflavone.

144. 6-(α-3-Piperidyl-benzyloxy)-isoflavone.

145. 7-(α-3-Piperidyl-benzyloxy)-isoflavone.

146. 5-(1-Methyl-3-piperidyl-methoxy)-isoflavone.

147. 6-(1-Methyl-3-piperidyl-methoxy)-isoflavone.

148. 7-(1-Methyl-3-piperidyl-methoxy)-isoflavone, hydrochloride, m.p.257°-260°.

149. 5-(α-1-Methyl-3-piperidyl-benzyloxy)-isoflavone.

150. 6-(α-1-Methyl-3-piperidyl-benzyloxy)-isoflavone.

151. 7-(α-1-Methyl-3-piperidyl-benzyloxy)-isoflavone, hydrochloride,m.p. 143°-145°.

152. 5-[2-(2-Piperidyl)-ethoxy]-isoflavone.

153. 6-[2-(2-Piperidyl)-ethoxy]-isoflavone.

154. 7-[2-(2-Piperidyl)-ethoxy]-isoflavone.

155. 5-[1-Phenyl-2-(2-piperidyl)-ethoxy]-isoflavone.

156. 6-[1-Phenyl-2-(2-piperidyl)-ethoxy]-isoflavone.

157. 7-[1-Phenyl-2-(2-piperidyl)-ethoxy]-isoflavone.

158. 5-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavone.

159. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavone.

160. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-isoflavone, hydrochloride, m.p.206°-207°.

161. 5-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-isoflavone.

162. 6-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-isoflavone.

163. 7-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]isoflavone.

164. 5-(4-Hexahydroazepinyloxy)-isoflavone.

165. 6-(4-Hexahydroazepinyloxy)-isoflavone.

166. 7-(4-Hexahydroazepinyloxy)-isoflavone.

167. 5-(1-Methyl-4-hexahydroazepinyloxy)-isoflavone.

168. 6-(1-Methyl-4-hexahydroazepinyloxy)-isoflavone.

169. 7-(1-Methyl-4-hexahydroazepinyloxy)-isoflavone.

170. 5-(3-Methyl-4-hexahydroazepinyloxy)-isoflavone.

171. 6-(3-Methyl-4-hexahydroazepinyloxy)-isoflavone.

172. 7-(3-Methyl-4-hexahydroazepinyloxy)-isoflavone.

173. 5-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavone.

174. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavone.

175. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-isoflavone.

176. 5-(1-Phenyl-3-methylaminopropoxy)-1-tetralone.

177. 6-(1-Phenyl-3-methylaminopropoxy)-1-tetralone.

178. 7-(1-Phenyl-3-methylaminopropoxy)-1-tetralone.

179. 5-(1-Phenyl-3-dimethylaminopropoxy)-1-tetralone.

180. 6-(1-Phenyl-3-dimethylaminopropoxy)-1-tetralone.

181. 7-(1-Phenyl-3-dimethylaminopropoxy)-1-tetralone, hydrochloride,m.p. 167°-169°.

182. 5-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-1-tetralone.

183. 6 (1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-1-tetralone, Rf 0.4(ethyl acetate).

184. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-1-tetralone,hydrochloride, m.p. 178°-180°.

185. 5-(3-Piperidyl-methoxy)-1-tetralone.

186. 6-(3-Piperidyl-methoxy)-1-tetralone.

187. 7-(3-Piperidyl-methoxy)-1-tetralone.

188. 5-(α-3-Piperidyl-benzyloxy)-1-tetralone.

189. 6-(α-3-Piperidyl-benzyloxy)-1-tetralone.

190. 7-(α-3-Piperidyl-benzyloxy)-1-tetralone.

191. 5-(1-Methyl-3-piperidyl-methoxy)-1-tetralone.

192. 6-(1-Methyl-3-piperidyl-methoxy)-1-tetralone.

193. 7-(1-Methyl-3-piperidyl-methoxy)-1-tetralone.

194. 5-(α-1-Methyl-3-piperidyl-benzyloxy)-1-tetralone.

195. 6-(α-1-Methyl-3-piperidyl-benzyloxy)-1-tetralone.

196. 7-(α-1-Methyl-3-piperidyl-benzyloxy)-1-tetralone.

197. 5-[2-(2-Piperidyl)-ethoxy]-1-tetralone.

198. 6-[2-(2-Piperidyl)-ethoxy]-1-tetralone.

199. 7-[2-(2-Piperidyl)-ethoxy]-1-tetralone.

200. 5-[1-Phenyl-2-(2-piperidyl)-ethoxy]-1-tetralone.

201. 6-[1-Phenyl-2-(2-piperidyl)-ethoxy]-1-tetralone.

202. 7-[1-Phenyl-2-(2-piperidyl)-ethoxy]-1-tetralone.

203. 5-[2-(1-Methyl-2-piperidyl)-ethoxy]-1-tetralone.

204. 6-[2-(1-Methyl-2-piperidyl)-ethoxy]-1-tetralone.

205. 7-[2-(1-Methyl-2-piperidyl)-ethoxy]-1-tetralone, hydrochloride,m.p. 188°-190°.

206. 5-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-1-tetralone.

207. 6-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-1-tetralone.

208. 7-[1-Phenyl-2-(1-methyl-2-piperidyl)-ethoxy]-1-tetralone.

209. 5-(4-Hexahydroazepinyloxy)-1-tetralone.

210. 6-(4-Hexahydroazepinyloxy)-1-tetralone.

211. 7-(4-Hexahydroazepinyloxy)-1-tetralone.

212. 5-(1-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

213. 6-(1-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

214. 7-(1-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

215. 5-(3-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

216. 6-(3-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

217. 7-(3-Methyl-4-hexahydroazepinyloxy)-1-tetralone.

218. 5-(1,3-Dimethyl-4-hexahydroazepinyloxy)-1-tetralone.

219. 6-(1,3-Dimethyl-4-hexahydroazepinyloxy)-1-tetralone.

220. 7-(1,3-Dimethyl-4-hexahydroazepinyloxy)-1-tetralone.

EXAMPLES 221 to 313

The following are obtained analogously to Example 1 from thecorresponding Na phenolates and the corresponding chloroamines orbromoamines:

221. 6-(1-Cyclopropyl-3-dimethylaminopropoxy)-isoflavone.

222. 7-(1-Cyclopropyl-3-dimethylaminopropoxy)-isoflavone.

223. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-isoflavone.

224. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-isoflavone,hydrochloride, m.p. 217°.

225. 6-(1-p-Chlorophenyl-3-dimethylaminopropoxy)-isoflavone.

226. 7-(1-p-Chlorophenyl-3-dimethylaminopropoxy)-isoflavone,hydrochloride, m.p. 247°.

227. 6-(1-p-Methoxyphenyl-3-dimethylaminopropoxy)-isoflavone.

228. 7-(1-p-Methoxyphenyl-3-dimethylaminopropoxy)-isoflavone, m.p.111°-113°.

229. 6-(1-p-Methylthiophenyl-3-dimethylaminopropoxy)-iso-flavone.

230. 7-(1-p-Methylthiophenyl-3-dimethylaminopropoxy)-isoflavone.

231. 6-(1-Phenyl-3-dimethylaminopropoxy)-4'-methoxy-flavan,hydrochloride, m.p. 166°-168°.

232. 7-(1-Phenyl-3-dimethylaminopropoxy)-4'-methoxy-flavan.

233.3-Methyl-6-(1-phenyl-3-dimethylaminopropoxy)-3',4'-methylenedioxy-flavanone,hydrochloride, m.p. 80°-120°.

234.3-Methyl-7-(1-phenyl-3-dimethylaminopropoxy)-3',4'-methylenedioxy-flavanone.

235.cis-3-Ethyl-6-(1-phenyl-3-dimethylaminopropoxy)-4'-methoxy-flavanone, Rf0.55.

236.trans-3-Ethyl-6-(1-phenyl-3-dimethylaminopropoxy)-4'-methoxy-flavanone,Rf 0.57.

237. cis-3-n-Propyl-6-(1-phenyl-3-dimethylaminopropoxy)-flavanone, Rf0.44.

238. 3-tert.-Butyl-6-(1-phenyl-3-methylaminopropoxy)-chromone.

239. 3-tert.-Butyl-7-(1-phenyl-3-methylaminopropoxy)-chromone.

240. 3-tert.-Butyl-6-(1-phenyl-3-dimethylaminopropoxy)-chromone.

241. 3-tert.-Butyl-7-(1-phenyl-3-dimethylaminopropoxy)-chromone.

242.3-tert.-Butyl-6-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

243.3-tert.-Butyl-7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

244. 3-tert.-Butyl-6-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

245. 3-tert.-Butyl-7-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

246. 3-tert.-Butyl-6-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

247. 3-tert.-Butyl-7-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

248. 3-tert.-Butyl-6-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

249. 3-tert.-Butyl-7-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

250. 2-Cyclopentyl-6-(1-phenyl-3-methylaminopropoxy)-chromone.

251. 2-Cyclopentyl-7-(1-phenyl-3-methylaminopropoxy)-chromone.

252. 2-Cyclopentyl-6-(1-phenyl-3-dimethylaminopropoxy)-chromone.

253. 2-Cyclopentyl-7-(1-phenyl-3-dimethylaminopropoxy)-chromone.

254.2-Cyclopentyl-6-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

255.2-Cyclopentyl-7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

256. 2-Cyclopentyl-6-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

257. 2-Cyclopentyl-7-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

258. 2-Cyclopentyl-6-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

259. 2-Cyclopentyl-7-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

260. 2-Cyclopentyl-6-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

261. 2-Cyclopentyl-7-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

262. 3-Cyclopentyl-6-(1-phenyl-3-methylaminopropoxy)-chromone.

263. 3-Cyclopentyl-7-(1-phenyl-3-methylaminopropoxy)-chromone.

264. 3-Cyclopentyl-6-(1-phenyl-3-dimethylaminopropoxy)-chromone.

265. 3-Cyclopentyl-7-(1-phenyl-3-dimethylaminopropoxy)-chromone.

266.3-Cyclopentyl-6-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

267.3-Cyclopentyl-7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

268. 3-Cyclopentyl-6-[α-1-(methyl-3-piperidyl)-benzyloxy]-chromone.

269. 3-Cyclopentyl-7-[α-1-(methyl-3-piperidyl)-benzyloxy]-chromone.

270. 3-Cyclopentyl-6-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

271. 3-Cyclopentyl-7-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

272. 3-Cyclopentyl-6-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

273. 3-Cyclopentyl-7-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

274. 2-Cyclohexyl-6-(1-phenyl-3-methylaminopropoxy)-chromone.

275. 2-Cyclohexyl-7-(1-phenyl-3-methylaminopropoxy)-chromone.

276. 2-Cyclohexyl-6-(1-phenyl-3-dimethylaminopropoxy)-chromone.

277. 2-Cyclohexyl-7-(1-phenyl-3-dimethylaminopropoxy)-chromone.

278. 2-Cyclohexyl-6-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

279. 2-Cyclohexyl-7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

280. 2-Cyclohexyl-6-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

281. 2-Cyclohexyl-7-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

282. 2-Cyclohexyl-6-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

283. 2-Cyclohexyl-7-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

284. 2-Cyclohexyl-6-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

285. 2-Cyclohexyl-7-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

286. 3-Cyclohexyl-6-(1-phenyl-3-methylaminopropoxy)-chromone.

287. 3-Cyclohexyl-7-(1-phenyl-3-methylaminopropoxy)-chromone.

288. 3-Cyclohexyl-6-(1-phenyl-3-dimethylaminopropoxy)-chromone.

289. 3-Cyclohexyl-7-(1-phenyl-3-dimethylaminopropoxy)-chromone.

290. 3-Cyclohexyl-6-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

291. 3-Cyclohexyl-7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-chromone.

292. 3-Cyclohexyl-6-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

293. 3-Cyclohexyl-7-[α-(1-methyl-3-piperidyl)-benzyloxy]-chromone.

294. 3-Cyclohexyl-6-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

295. 3-Cyclohexyl-7-[2-(1-methyl-2-piperidyl)-ethoxy]-chromone.

296. 3-Cyclohexyl-6-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

297. 3-Cyclohexyl-7-(1,3-dimethyl-4-hexahydroazepinyloxy)-chromone.

298.3-Methyl-6-(1-phenyl-3-dimethylaminopropoxy)-3',4'-methylenedioxy-flavone,m.p. 74°-76°.

299.3-Methyl-7-(1-phenyl-3-dimethylaminopropoxy)-3',4'-methylenedioxy-flavone.

300. 2-Ethyl-6-(1-phenyl-3-dimethylaminopropoxy)isoflavone.

301. 2-Ethyl-7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone,hydrochloride, m.p. 226°-228°.

302. 6-(1-Phenyl-3-dimethylaminopropoxy)-4'-fluoroisoflavone.

303. 7-(1-Phenyl-3-dimethylaminopropoxy)-4'-fluoroisoflavone, m.p.112°-113°; hydrochloride, m.p. 234°-235°.

304. 6-(1-Phenyl-3-dimethylaminopropoxy)-4'-chloroisoflavone.

305. 7-(1-Phenyl-3-dimethylaminopropoxy)-4'-chloroisoflavone,hydrochloride, m.p. 259°-260°.

306. 6-(1-Phenyl-3-dimethylaminopropoxy)-3'-trifluoromethyl-isoflavone.

307. 7-(1-Phenyl-3-dimethylaminopropoxy)-3'-trifluoromethyl-isoflavone,hydrochloride, m.p. 174°-176°.

308. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-4'-fluoro-isoflavone.

309. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-4'-fluoro-isoflavone,m.p. 121°-123°; hydrochloride, m.p. 229°-230°.

310. 6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-4'-chloro-isoflavone.

311. 7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-4'-chloro-isoflavone,hydrochloride, m.p. 213°-215°.

312.6-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-3'-trifluoromethyl-isoflavone.

313.7-(1-p-Fluorophenyl-3-dimethylaminopropoxy)-3'-trifluoromethyl-isoflavone,hydrochloride, m.p. 174°-176°.

EXAMPLE 314

23.8 g of 7-hydroxyisoflavone is dissolved in 500 ml of absolutetoluene, 7.1 ml of thallium-(I) ethylate are added and the mixture isstirred for 1 hour at 20°. After evaporation, the residue is dissolvedin 100 ml of absolute acetonitrile, 20 g of1-chloro-1-phenyl-3-dimethylaminopropane is added and the mixture isboiled for 3 hours while stirring and is evaporated. Working up in thecustomary manner gives 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone.M.p. 128°-130°.

EXAMPLE 315

2.7 g of azodicarboxylic acid ethyl ester is dissolved in 25 ml of THF,4 g of triphenylphosphine is added, while cooling and stirring, asolution of 2 g of 1-chloro-1-phenyl-3-dimethylaminopropane in 15 ml ofTHF is then added dropwise, followed by a solution of 2.38 g of7-hydroxyisoflavone in 10 ml of THF and the mixture is stirred for 2hours at 0°. After being allowed to stand overnight at 20°, the mixtureis worked up in the customary manner. This gives7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone. M.p. 128°-130°.

EXAMPLE 316

200 ml of 50% aqueous sodium hydroxide solution and 1 g oftriethylbenzylammonium chloride are added to a solution of 23.8 g of7-hydroxyisoflavone in 100 ml of CH₂ Cl₂, 20 g of1-chloro-1-phenyl-3-dimethylaminopropane is added dropwise whilestirring and stirring is continued for a further hour. Working up in thecustomary manner gives 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone.M.p. 128°-130°.

EXAMPLE 317

A solution of 20 g of7-(1-phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavone in 400 ml ofmethanol is hydrogenated over 3 g of 5% Pd-on-C at 20° and 1 atmosphereuntil absorption of hydrogen ceases. The mixture is filtered andevaporated to give 7-(1-phenyl-3-methylaminopropoxy)-isoflavone,hydrochloride, m.p. 210°-211°.

EXAMPLE 318

30 g of formic acid, is added dropwise to 38.5 g of7-(1-phenyl-3-methylaminopropoxy)-isoflavone, while stirring andcooling, and 7 g of 25% formaldehyde solution is then added dropwise at20°. The mixture is heated on a waterbath until evolution of gas ceasesand is cooled, poured onto ice and worked up in the customary manner togive 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone. M.p. 128°-130°.

EXAMPLE 319

12 g of allyl bromide and 26 g of anhydrous potassium carbonate areadded to a solution of 38.5 g of7-(1-phenyl-3-methylaminopropoxy)-isoflavone in 1 l of absolute tolueneand the mixture is boiled for 20 hours, cooled, poured into water andworked up in the customary manner to give7-(1-phenyl-3-N-allyl-N-methylaminopropoxy)-isoflavone. Hydrochloride,m.p. 192°-194°.

EXAMPLES 320 TO 326

The following are obtained analogously to Example 319 using allylbromide, n-butyl iodide, cyclopropylmethyl chloride or benzyl bromide:

320. 6-(1-Phenyl-3-N-allyl-N-methylaminopropoxy)-isoflavone.

321. 6-(1-Phenyl-3-N-n-butyl-N-methylaminopropoxy)-isoflavone.

322. 7-(1-Phenyl-3-N-n-butyl-N-methylaminopropoxy)-isoflavone.

323. 6-(1-Phenyl-3-N-cyclopropylmethyl-N-methylaminopropoxy)-isoflavone.

324. 7-(1-Phenyl-3-N-cyclopropylmethyl-N-methylaminopropoxy)-isoflavone,hydrochloride, m.p. 225°-227°.

325. 6-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavone.

326. 7-(1-Phenyl-3-N-benzyl-N-methylaminopropoxy)-isoflavone.

EXAMPLES 327 TO 331

The following are obtained analogously to Example 1 from thecorresponding Na phenolates and the corresponding basic chlorides:

327. 6-(1-Cyclopropyl-3-methylaminopropoxy)-flavone, Rf 0.45 (8:2chloroform/triethylamine).

328. 6-(1-Phenyl-3-dimethylaminopropoxy)-4'-methoxyflavone, m.p.125°-127°,

329. 6-(1-Phenyl-3-dimethylaminopropoxy)-3',4'-methylenedioxy-flavone,m.p. 159°-160°.

330. 7-(1-Cyclopropyl-3-methylaminopropoxy)-chroman, Rf 0.24 (methanol).

331. 7-(1-Cyclopropyl-3-dimethylaminopropoxy)-chroman, Rf 0.74 (8:2chloroform/triethylamine).

The following examples relate to pharmaceutical formulations containingamines of Formula I or their acid addition salts.

Example A: Tablets

A mixture of 1 kg of 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavonehydrochloride, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talcand 0.1 kg of magnesium stearate is compressed in a customary manner togive tablets, in such a way that each tablet contains 10 mg of activecompound.

Example B: Dragees

Tablets are compressed analogously to Example A and are then coated in acustomary manner with a coating consisting of sucrose, potato starch,talc, tragacanth and colorant.

Example C: Capsules

2 kg of 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone hydrochloride isfilled into hard gelatine capsules in a customary manner in such a waythat each capsule contains 20 mg of the active compound.

Example D: Ampoules

A solution of 1 kg of 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavonehydrochloride in 30 l of twice-distilled water is filtered under sterileconditions and filled into ampoules, which are lyophilized under sterileconditions and sealed under sterile conditions. Each ampoule contains 10mg of active compound.

Tablets, dragees, capsules and ampoules containing one or more of theremaining active compounds of Formula I and/or their physiologicallyacceptable acid addition salts can be obtained analogously.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A basic ether of the formula ##STR4## wherein Zis CH₃ --NR² --CH₂ CH₂ --CHR¹ --, R¹ is cyclopropyl or Ar; R² is H,alkyl of 1-4 C atoms, alkenyl of 2-4 C atoms, cycloalkylalkyl of 4-8 Catoms or benzyl; R³ is H or Ar; R⁴ is H or alkyl of 1-4 C atoms, Y is--O--CQ¹ ═CQ² --CO--, Q¹ and Q² are independently each H, alkyl of 1-4 Catoms, cycloalkyl or alkylcycloalkyl each or 3-6 total C atoms or Ar;and Ar is phenyl or phenyl substituted by F, Cl, alkoxy or alkylthio,each of 1-4 C atoms, methylenedioxy or CF₃ ; with the proviso that whenZ is (CH₃)₂ N--CH₂ CH₂ --CHR¹ in 7-position and Y is --O--C(C₆H₅)═CH--CO-- or --O--C(C₆ H₅)═C(CH₃)--CO--, R¹ is cyclopropyl, or phenylsubstituted by F, Cl, alkoxy or alkylthio, each of 1-4 C atoms,methylenedioxy or CF₃ ;or a physiologically acceptable acid additionsalt thereof.
 2. A compound of claim 1, wherein R¹ is Ar, Q² is H and Q¹is Ar.
 3. An ether of claim 1 wherein, R¹ is phenyl; R² is H, methyl orbenzyl; Y is --O--CAr═CQ⁴ --CO--, --O--CH═CAr--CO--, Ar is phenyl,p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl,3,4-methylenedioxyphenyl or m-trifluoromethylphenyl; and Q⁴ is H oralkyl of 1-3 C atoms.
 4. An ether of claim 1 wherein, R¹ is phenyl; R²is H, methyl or benzyl; and Y is --O--C(C₆ H₅)═CH--CO--, or --O--CH═C(C₆H₅)--CO--.
 5. An ether of claim 1 wherein, R¹ is phenyl; R² is H, methylor benzyl; and Y is --O--CH═C(C₆ H₅)--CO--. 6.6-(1-Phenyl-3-dimethylaminopropoxy)-flavone, a compound of claim
 1. 7. Apharmaceutical composition comprising an antidepressantly effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 8. A composition of claim 7 containing 2-500 mg of theantidepressantly active compound.
 9. A method of treating depression ina patient in need of such treatment comprising administering to thepatient an antidepressantly effective amount of a compound of claim 1.